Preparation of powder agglomerates

ABSTRACT

The invention relates to a method of producing an agglomerate of drug and solid binder. The process involves producing individual agglomerate particles and then converting the convertible amorphous content of same, following agglomeration, by the application of, for example, moisture. Agglomerates capable of conversion as well as the finished agglomerates and oral and nasal dosing systems including same are also contemplated. The process produces agglomerates which are rugged but which will produce an acceptable fine particle fraction during dosing.

FIELD OF THE INVENTION

[0001] The present invention relates broadly to the formation ofagglomerates. More specifically, the present invention relates to thefield of pharmaceutical dosage form design and, in particular, theproduction of unique agglomerated dosage forms for administration ofpharmacologically active agents to patients. The formulations inaccordance with this invention are particularly well suited for oraland/or nasal inhalation.

INTRODUCTION TO THE INVENTION

[0002] There are several known methods of treating diseases andconditions of the upper and lower airway passages and the lungs. Theseconditions include, for example, asthma and rhinitis. One such techniqueinvolves administering certain pharmacologically active agents or drugssuch as, for example, mometasone furoate, topically to the airwaypassages or lungs in an immediately useable form. Mometasone furoate isa topically effective, steroidal anti-inflammatory.

[0003] Oral inhalation therapy is one method of delivering suchtopically active drugs. This form of drug delivery involves the oraladministration of a dry powdered drug directly to the afflicted area ina form which is readily available for immediate benefit.

[0004] However, inhalation therapy is a particularly demanding dosingsystem and it involves its own set of unique design and performanceproblems. Amongst those problems is a concern over the accuracy andrepeatability of dosing. One must try to ensure that the same amount ofdrug is administered each and every time. Moreover, unlike pills,capsules and creams, oral inhalation therapy must concern itself withnot only the dosage form itself, but also a drug delivery device and theinteraction between them. One has only to consider over-the-counternasal sprays to understand this problem. When one squeezes aconventional squeeze bottle, it is difficult to apply the same amount offorce each and every time. With even a slight difference in force,differences in the amount of drug administered can result. Even withsomewhat more consistent pump style spray applicators, variations indosing can occur. While such variation is usually not a problem whenadministering OTC nasal sprays, variation should be minimized wherepossible when administering prescription medications for such seriousconditions as asthma. The dangers of over-medicating or under-medicatingand the consequences of such unwanted deviation can be profound. Theproblem becomes even more complex when the size of the doses are assmall as they often are in oral inhalation therapy.

[0005] To help mitigate these problems, companies such as ScheringCorporation have developed complex and highly accurate inhaler systemsfor administering powdered medications such as those described in PCTInternational Publication No. WO 94/14492, which was published on Jul.7, 1994, the text of which is hereby incorporated by reference. Suchinhaler systems were designed to meter out an exact dose of a powderedmedication using a dosing hole of a specific size. The hole iscompletely filled with drug prior to administration and the entirecontents of the dosing hole are then delivered to the patient through anozzle. The dosing hole is then filled again for the next dose. Thesedevices have been specifically designed to remove, as much as possible,human error and mechanically induced variability in dosing.

[0006] While such devices represent a significant advance in oralinhalation therapy, there are still some circumstances in which problemsmay remain. These problems often center on the properties of thepharmacologically active agent and their interaction with the inhaler.For example, certain drugs are not “free-flowing” and that may make itdifficult to move the drug from storage in a reservoir, to measurementin a dosing hole, to delivery from the inhaler. Other drugs may sufferfrom electrostatic charge problems or may exhibit an unacceptable degreeof cohesive force. Such drugs may be “sticky,” even when in powderedform. These drugs may clog the inhaler/applicator, affecting its abilityto properly meter the intended amount of medication. Such powders mayalso adhere to the nozzle of the applicator, thus reducing the amount ofmedication actually delivered. This is often referred to as “hang up.”Drugs may also be “fluffy” which makes handling and loading sufficientdrug into a dosing hole a real challenge. To make matters even worse,these and other physical properties of various pharmacologically activeagents may vary within a single batch of material. This can defeatattempts to compensate.

[0007] Related problems may also result based upon the small size of theparticles which are generally used in inhalation therapy. Inhalationtherapy commonly involves drug particles which are on the order of 10 μmor below. This ensures adequate penetration of the medicament into thelungs of the patient as well as good topical coverage. In order toprovide adequate dispensing of such medicines, tight control must bemaintained on the size of the particles of the drug. However, powders ofthis size can be extremely difficult to work with, particularly whensmall dosages are required. Such powders are typically not free-flowingand are usually light, dusty or fluffy in character, creating problemsduring handling, processing, and storing. In addition, it can bedifficult to repeatedly and accurately load such materials into thedosing hole of an inhaler. Thus not only the properties of the drug, butalso the required size of the therapeutic particulate, can combine tocause considerable problems in terms of handling and dosing.

[0008] One method of improving the ability to administer fine powderedmedicaments is by the inclusion of dry excipients such as, for example,dry lactose. However, it has been determined that when particularlysmall doses of medication are required, such as under about 100-200 μgof drug, the inclusion of conventional excipients may not adequatelycompensate for the problems associated with the use of fine drugparticles. In addition, dry excipients as commonly used, generally haveparticle sizes which are significantly larger than the particle size ofthe drug. Unfortunately, the use of such large particles can have asignificant impact on the amount of drug delivered from dose to dose.Moreover, the intended benefits of the use of such excipients begins todiminish as the size of the dose decreases. Therefore, drug hang up orretention within the metering device or the inhalation nozzle and otherhandling issues can become an increasing problem.

[0009] Alternatively, drug products can be processed to formagglomerates or pellets which are generally more free-flowing and bulky.One method of agglomerating drugs is described in PCT InternationalPublication No. WO 95/09616, published on Apr. 13, 1995. As describedtherein, agglomerates of finely divided powder medicaments, such asmicronized powders having a particle size smaller than 10 μm, can beproduced which require no binders. However, they can be formed withexcipients. These agglomerates can then be administered through aninhaler for powdered medications.

[0010] The ability to create particles without a binder is significantto inhalation therapy and can pose a great advantage over othertechniques which use water or other traditional binders in agglomerateformation. Agglomerates of pure drug can provide great advantages whenformulating and handling powders. It has been found, however, that atdoses of about 100-200 μg, of a drug such as mometasone furoate, andbelow, agglomerates of pure drug can suffer from hang up and dosingvariability can be a genuine concern. Even in dosing systems designed toprovide relatively larger doses of pharmacologically active agent, suchas about 400 μg or above, the resulting agglomerates of pure drug canstill suffer from integrity problems. These agglomerates are stillrelatively soft and can be crushed during metering thereby providingvariability in dosing. The material can also be broken fairly readilyby, for example, dropping an inhaler from a height of about four feet.This would prematurely result in the formation of smaller particleswhich are more difficult to handle. In fact, it is the handlingdifficulties of the fine drug particles that necessitated agglomerationin the first place.

[0011] If binder-containing agglomerates are to be used, suchagglomerates can be made by the methods described in, for example, U.S.Pat. No. 4,161,516 and GB Patent 1,520,247 which disclose the use ofcertain binding materials, including water, for the production ofagglomerates for oral inhalation. According to the processes describedtherein, prior to agglomeration, the moisture content of certain “selfagglomerating” or hygroscopic micronized drugs are elevated. After themicronized powder has been elevated to the desired water content level,it is agglomerated. Non-hygroscopic materials must be bound with moretraditional binders as described therein. Similarly, WO 95/05805discloses a process for forming agglomerates where a mixture ofhomogeneous micronized materials are treated with water vapor toeliminate any convertible amorphous content which may destabilize at alater point. After treatment with water vapor, the now crystallinematerial is agglomerated. However, this application warns that if thevapor exposure is conducted after agglomeration, the product is “uselessin an inhalation device.”

[0012] The effect of moisture on the tableting characteristics ofanhydrous lactose is discussed in Sebhatu, Elamin and Ahlneck, “Effectof Moisture Sorption on Tableting Characteristics and Spray Dried (15%Amorphous) Lactose,” Pharmaceutical Research, Vol.11, No. 9, pages1233-1238 (1994). The article does not, however, discuss the formationof agglomerates, or the production of agglomerates which can yield anacceptable “fine particle fraction,” also known as a “respirablefraction” when administered as part of oral inhalation therapy.

[0013] The Sebhatu et al. article uses a method for determiningamorphous content which is more fully described by T. Sebhatu, M.Angberg and C. Ahlneck, “Assessment of the Degree of Disorder inCrystalline Solids by Isothermal Microcalorimetry,” InternationalJournal of Pharmaceutics, Vol.104, pages 135-144 (1994). An isothermalmicrocalorimeter is used to determine the specific heat ofcrystallization for totally amorphous lactose, and then the “percentdisorder” (denoted herein, for purposes of the present invention,“percent convertible amorphous content”) is determined by dividing thespecific heat of crystallization for a partially amorphous sample by thevalue previously obtained for the totally amorphous material, thenmultiplying by 100. The equipment described for making thesemeasurements is satisfactory for use in the present invention.

SUMMARY OF THE INVENTION

[0014] The present invention provides an improved agglomerate and aprocess for making same. By design, the present invention takesadvantage of the use of a solid binder in combination with fine drugparticles and the amorphous characteristics which can be imparted to thesolid binder and/or the drug. This occurs just when others would seek toeliminate such characteristics. The present invention also results inunique crystalline agglomerates of a first material and a solid binderwhich are free-flowing, sufficiently bulky and sufficiently stable to behandled, metered and delivered, even in extremely small doses. At thesame time, the interparticulate bond strength of the agglomerates issufficiently fragile to allow the agglomerates to break apart duringadministration through an inhaler so as to provide an acceptable fineparticle fraction. All of this is accomplished substantially without theuse of an additional, more conventional binder.

[0015] In particular, the present invention provides a process ofproducing agglomerates. The process includes providing particles of atleast one first material, generally a pharmacologically active agent,and providing particles of at least one solid binder. At least one ofthese two particles, the drug or the solid binder, includes as partthereof, a preselected amount of a convertible amorphous content whichis sufficient to, upon crystallization thereof, allow for the formationof generally crystalline, agglomerates. The predetermined convertibleamorphous content of the binder and/or the drug is capable of beingconverted to a crystalline form upon exposure to a preselected stimuluswhich includes, among other things, humidity.

[0016] The particles are then agglomerated while maintaining thepreselected or predetermined amount of convertible amorphous content.After agglomeration is complete, the convertible amorphous contentwithin the agglomerates is exposed to the preselected stimulus and isconverted to a crystalline form. By “crystalline,” it is understood thatthe agglomerates of the present invention can still contain someamorphous content, predominantly non-convertible amorphous phase with orwithout some amount of unconverted convertible amorphous content. Thelatter is to be minimized. Without wishing to be bound by any particularscientific theory, it is believed that the conversion of the convertibleamorphous content creates crystalline bonds between the particles. Thesebonds are strong enough to preserve the integrity of the agglomeratesduring handling, storage and metering. However, they are soft enough tobe overcome by commercially available inhalers so as to provide anacceptable fine particle fraction upon dosing.

[0017] It is an important aspect of the present invention that theagglomerates contain a certain content of convertible amorphous contentduring formation. “Convertible” means that the amorphous content, whenexposed to certain predetermined or preselected stimuli, will convertfrom amorphous to crystalline form. This convertible amorphous contentcan be present as part of the drug, part of the solid binder, or both.The distribution of the amorphous content on the particles is generallyunimportant so long as sufficient convertible amorphous content ispresent, preferably substantially homogeneously, throughout the system.

[0018] The fact that the solid binder may or may not contain anyconvertible amorphous content is not important in and of itself. In suchinstances, the solid binder still imparts certain advantageousproperties to the resulting agglomerates in terms of their ability toflow freely, their bulk density, their strength and the ability toretard hang-up.

[0019] In a more preferred embodiment, the present invention provides amethod of producing agglomerates of a pharmacologically active agentincluding the steps of providing of at least one pharmacologicallyactive agent having an average particle size of below about 10 μm and atleast one solid binder. Preferably, the majority of the solid binderalso exists as particles of less than about 10 μm. Generally, the binderhas a preselected amount of convertible amorphous content which issufficient to allow for the formation of agglomerates with thepharmacologically active agent upon crystallization by exposure to apreselected stimulus such as atmospheric moisture. The next stepinvolves forming a substantially homogeneous mixture of the particleswhile maintaining the preselected amount of convertible amorphouscontent. The mixture is then agglomerated while still maintaining thepreselected amount of amorphous content. Finally, the convertibleamorphous content of the solid binder and/or drug within theagglomerates is converted to a crystalline form by exposure to thepreselected stimulus. The resulting agglomerates are free-flowing andare characterized by bridges or bonds between the particles such as, forexample, between the pharmacologically active agent and the solidbinder, (or even between the particles of the solid binder themselves),which are strong enough to withstand handling, but weak enough to allowfor the delivery of an acceptable fine particle fraction of freeparticles of the pharmacologically active agent.

[0020] The result of this preferred aspect of the present invention isthe creation of a dosage form of a pharmacologically active agent usefulas part of oral and/or nasal inhalation therapy. The dosage formincludes agglomerates of particles of the pharmacologically active agentand particles of crystalline solid binder. The particles preferably havean average particle size of 10 μm or less.

[0021] The ratio of drug to binder in the agglomerate can vary widelydepending upon the amount of drug to be administered, the fine particlefraction desired and the amount of and relative distribution of,convertible amorphous content present as part of the drug and/or binder.In fact, the ratio of drug to binder can range from between about 1000:1to 1:1000 (drug:binder). However, preferably, the drug and binder arepresent in a ratio of between 100:1 to 1:500 and even more preferablybetween 100:1 to 1:300.

[0022] The agglomerates generally range in sizes from between about 100to about 1500 μm and an average size of between 300 and 1000 μm. Thebulk density of the resulting agglomerates is between about 0.2 andabout 0.4 g/cm³. Preferably the ratio of drug to solid binder rangesfrom between about 20:1 to about 1:20 and most preferably 1:3 to 1:10.The agglomerates also preferably have an average size of between about300 and about 800 μm and more preferably between about 400 and about 700μm.

[0023] In another aspect of the present invention there is provided anintermediate agglomerate useful for producing a free-flowing crystallineagglomerate dosage form of a pharmacologically active agent. Theintermediate agglomerate includes particles of a pharmacologicallyactive agent and particles of solid binder, preferably anhydrouslactose. The binder and/or the drug particles include a preselectedamount of convertible amorphous content which is sufficient to allow forthe formation of crystalline agglomerates upon exposure to a preselectedstimulus. The particles of pharmacologically active agent and particlesof the binder have an average particle size of about 10 μm or below, andeach is provided in a ratio of between about 100:1 and about 1:500 andeven more preferably between about 100:1 and about 1:300. The resultingagglomerates range in size from between about 100 μm to about 1500 μmand have an average size of between 300 and 1000 μm. Their bulk densitygenerally ranges from between about 0.2 and about 0.4 g/cm³.

[0024] These intermediate agglomerates are too weak to withstand normalhandling and thus they are not suitable for a dosage form. They alsohave a relatively high rate of hang up in the nozzle of an inhaler. Suchagglomerates are also not stable. Over time, they will convert, in anuncontrolled manner, to a crystalline form. This yields a higher levelof variability in terms of bond strength and dosing uniformity. However,these amorphous agglomerates are very useful in the formation ofcrystalline dosage forms in which at least substantially all of theconvertible amorphous content is converted to a crystalline form byexposure to a preselected stimulus.

[0025] A particularly preferred aspect of the present invention is theprovision of a method of ensuring a higher level of dosing uniformityfor very small doses of orally inhaled pharmacologically active agentsor drugs (about 400 μg of drug or below). The method includes metering adose of an agglomerated pharmacologically active agent as previouslydescribed and administering that dose of agglomerated pharmacologicallyactive agent to a patient in need thereof.

[0026] The present invention also provides a metered dose of apharmacologically active agent useful for administration by oralinhalation therapy. The metered dose can vary widely in size; includingup to about 50,000 μg of the pharmacologically active agent perinhalation. The ability to accommodate such a wide range of dosinglevels is a direct result of the advantages which inure from the use ofthe present invention to manufacture agglomerates. However, the presentinvention is most useful in the context of very small doses including upto about 400 μg of particulate pharmacologically active agent with thebalance being lactose binder. More particularly, the dose contains about100 μg of pharmacologically active agent or less. It is these smallerdosing levels which are the most demanding on dosage forms.

[0027] Oral inhalation of a pharmacologically active agent, aspreviously noted, can be demanding, not only on dosing equipment, butalso on formulations. The dosage form appears to need to simultaneouslymeet a number of criteria, many of which were thought to be mutuallyexclusive. For example, it is very important that the agglomerates beformed in a highly repeatable, consistent manner with very littlevariation in terms of size, drug content and interparticle bondstrength. The agglomerates must also be sufficiently solid to allow themto be worked, sieved, spheronized and otherwise manipulated withoutfalling apart. At the same time, the agglomerates must be sufficientlyweak so as to allow them to break apart during inhalation and yield, tothe extent possible, small, free particles of drugs in a manner which istherapeutically effective. For another example, the agglomerates must besufficiently free-flowing to allow them to be loaded into an inhaler,and metered through the inhaler and delivered, with as little residuebeing retained as possible. However, forming agglomerates of inherentlyfree-flowing materials can be difficult.

[0028] One of the most interesting aspects of the present invention isthe realization that attempting to balance these often competingperformance criteria is neither possible nor necessary. Instead, theinvention uses certain properties when those properties areadvantageous. Then, just when those same attributes would becomeliabilities, the agglomerate is changed fundamentally to eliminate thoseproperties entirely. In their place, a new crystalline agglomerate isrealized. This new agglomerate retains none of those properties of theformer agglomerates which were useful for agglomerate formation, butdetrimental to handling, measuring and administering.

[0029] Instead, the new agglomerates, after conversion of theconvertible amorphous content of the solid binder and/or the drug, arefree flowing and very consistent in terms of agglomerate size and sizedistribution. Furthermore, the agglomerates are sufficiently rugged toallow them to be handled, metered, and even dropped while within aninhaler without the adverse consequences found in the prior art. At thesame time, when used in combination with an inhaler that can generatesufficient force, the structural integrity of these rugged agglomeratescan be interrupted sufficiently so as to provide an acceptable fineparticle fraction.

[0030] Therefore, in accordance with another aspect of the presentinvention, there is provided a crystalline agglomerate of a drug with anaverage particle size of 10 μm or less and particles of a solid binder.These particles are bound together as a result of the conversion at aportion of a convertible amorphous region of either the drug, thebinder, or both. No additional binder is required. These agglomeratesare provided in combination with a nasal or oral inhaler which isconfigured so as to provide a fine particle fraction of drug particlesof at least 10%. In general, the agglomerates which result have a crushstrength of between about 50 mg and about 5,000 mg. More preferably, thecrystalline agglomerates in accordance with the present invention have acrush strength of between about 200 mg and about 1500 mg. Thus, theinhaler used for dosing these agglomerates will have to provide, as aminimum, sufficient force to overcome the inherent strength of theagglomerate so as to result in a fine particle fraction of at leastabout 10% or more. This means that at least 10% of the drug will bereduced to a fine particle fraction of particles having a size of 6.8 μmor less. It should come as no surprise that if an inhaler is configuredto provide at least a 10% fine particle fraction of the drug when theagglomerate strength is 5,000 mg, the same inhaler will provide a muchgreater fine particle fraction if used in combination with agglomeratesin accordance with the present invention having a strength of, forexample, 500 mg.

[0031] It has also been found that by providing a solid binder having asimilar range of particle sizes when compared to the particle size ofthe particles of drug, it is possible to obtain a substantiallyhomogeneous distribution of drug in each metered dose, even when themetered doses of drug are as small as about 400 μg or below.

[0032] In sum, it has been found that by converting the amorphouscontent of the binder or drug to a crystalline form within thepre-formed agglomerate, once agglomeration is complete, one can impartdesirable properties. When the amorphous content of the agglomerates isconverted to crystalline form, the agglomerates become stable. They are,indeed, less sensitive to factors such as humidity and temperature. Thecrystalline material is also free-flowing and exhibits reduced hang uprelative to the same agglomerates prior to conversion. It is easier toload into and empty from a dose hole and, therefore, provides forconsistent metering. This coupled with high stability and homogeneitymakes consistent dosing of very small doses possible.

[0033] Thus it has been found that, through the present invention, it ispossible to provide materials which are ideally suited for agglomerationjust when it is necessary to agglomerate such materials and it is alsopossible to produce agglomerates which are ideally suited foradministering pharmacologically active substances through an oralinhalation system.

[0034] Another important aspect of the present invention is a change inthe conventional perception of the amorphous content of particles. Theindustry has long known of the amorphous character imparted to certainmaterials by such processes as micronizing, spray drying, freeze dryingand ball milling. Some degree of amorphous character is unavoidablyimparted upon materials when the particle size is reduced using suchtechniques. However, because of the variability that can result fromsuch amorphous materials, the industry has long sought a way to minimizeor eliminate the creation of amorphous content during microparticleformation.

[0035] In fact, that is the very point of WO 95/05805. That PCTapplication seeks to form, as much as possible, a homogenous mixture ofparticles of as uniform characteristics as possible so as to insure theproduction of agglomerates having a more tightly controlled size. Thetheory appears to be that if one can insure a homogeneity in terms ofparticle size, mixture of particles and crystallinity, is easier tocontrol the resulting size and composition of agglomerates. Therefore,moisture is added to the particles, prior to agglomeration, to insurethat their entire convertible amorphous content is converted tocrystalline form.

[0036] In accordance with the present invention, however, it has beenfound that the amorphous character of the drug and/or binder can beharnessed to the formulator's advantage. By using the amorphous contentof the mixture as the binder, one can eliminate the need for additionalbinders. This can only be accomplished, however, where agglomerationoccurs prior to exposure of significant quantities of atmosphericmoisture. Once the particulate has been exposed to moisture, theconversion of the convertible amorphous content will prevent a solidstate agglomeration and a formation of direct intercrystalline bonds.

[0037] Moreover, it has been found that merely imparting such amorphouscontent upon particles is not sufficient. Certainly, it has long beenknown to micronized drugs. However, because of many drugs' naturalstability, they cannot be readily transformed to crystallineagglomerates as discussed herein. Rather, it has been discovered that byimparting a certain amount of amorphous character to a solid binder, abinder which is capable of being readily re-converted to a crystallineform, the advantages of the present invention can be realized. It hasbeen discovered that the use of a solid metastable material as a binderprovides advantages both when the binder is in its amorphous form andagain when it is in its crystalline form, so long as the various formsare intentionally used at the right time.

BRIEF DESCRIPTION OF THE DRAWINGS

[0038]FIG. 1 is a graph illustrating the water uptake of agglomerates ofthe present invention when exposed to humidity before and after beingsubjected to conversion.

[0039]FIG. 2 is a block diagram illustrating a manufacturing scheme foragglomerates of either lactose alone or mometasone furoate and lactose.

[0040]FIG. 3 is a graph illustrating the results of a 122 cm (48 inch.)drop test wherein: ∘ is inhaler 1,  is inhaler 2, ∇ is inhaler 3, ▾□ isinhaler 4, □

is inhaler 5, ▪ is inhaler 6, Δ is inhaler 7, ▴ is inhaler 8, ⋄ isinhaler 9, and ♦ is inhaler 10.

[0041]FIG. 4 is a graph illustrating the results of a control for a 122cm (48 inch.) drop test wherein: ∘ is inhaler 1,  is inhaler 2, ∇ isinhaler 3, ▾ is inhaler 4, □

is inhaler 5, ▪is inhaler 6, Δ is inhaler 7, ▴ is inhaler 8, ⋄ isinhaler 9, and ♦ is inhaler 10.

DETAILED DESCRIPTION OF THE INVENTION

[0042] An agglomerate in accordance with the present invention is abound mass of small particulates. The agglomerates include at least onefirst material and at least one solid binder. The first material, inaccordance with the present invention can be anything as, indeed, thepresent invention can be used broadly to make free-flowing agglomeratesfor any application including, medicine, cosmetics, food and flavoring,and the like. However, preferably, the first material is apharmacologically active agent or drug which is to be administered to apatient in need of some course of treatment. The pharmacologicallyactive agent may be administered prophylactically as a preventative orduring the course of a medical condition as a treatment or cure.

[0043] Most preferably, in accordance with the present invention, thepharmacologically active agent or drug is a material capable of beingadministered in a dry powder form to the respiratory system, includingthe lungs. For example, a drug in accordance with the present inventioncould be administered so that it is absorbed into the blood streamthrough the lungs. More preferably, however, the pharmacologicallyactive agent is a powdered drug which is effective to treat somecondition of the lungs or respiratory system directly and/or topically.Particularly preferred pharmacologically active agents in accordancewith the present invention include, without limitation, corticosteroidssuch as: mometasone furoate; beclomethasone dipropionate; budesonide;fluticasone; dexamethasone; flunisolide; triamcinolone;(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione;tipredane and the like. β-agonists (including β₁ and β₂-agonists)including, without limitation, salbutamol (albuterol), terbutaline,salmeterol, and bitolterol may also be administered. Formoterol (alsoknown as eformoterol) e.g., as the fumarate or tartrate, a highlyselective long-lasting β₂-adrenergic agonist having bronchospasmolyticeffect, is effective in the treatment of reversible obstructive lungailments of various genesis, particularly asthmatic conditions. Anotherlong-acting β-agonist which can be administered in accordance with thepresent invention is known as TA-2005, chemically identified as2(1H)-Quinolinone,8-hydroxy-5-[1-hydroxy-2-[[2-(4-(methoxyphenyl)-1-methylethyl]amino]ethyl]-monohydrochloride,[R—(R*,R*)]— also identified by Chemical Abstract Service RegistryNumber 137888-11-0 and disclosed in U.S. Pat. No. 4,579,854, the text ofwhich is hereby incorporated by reference. Anticholinergics such asipratropium bromide and oxitropium bromide may be used. So, too cansodium cromoglycate, nedocromil sodium and leukotriene antagonists suchas zafirlukast and praniukast. Bambuterol (e.g. as hydrochloride),fenoterol (e.g. hydrobromide), clenbuterol (e.g. as hydrochloride),procaterol (e.g. as hydrochloride), and broxaterol are highly selectiveβ₂-adrenergic agonists can be administered. Several of these compoundscould be administered in the form of pharmacologically acceptableesters, salts, solvates, such as hydrates, or solvates of such esters orsalts, if any. The term is also meant to cover both racemic mixtures aswell as one or more optical isomers. The drug in accordance with thepresent invention can also be an inhalable protein or a peptide such asinsulin, interferons, calcitonins, parathyroid hormones, granulocytecolony-stimulating factor and the like. “Drug” as used herein may referto a single pharmacologically active entity, or to combinations of anytwo or more, an example of a useful combination being a dosage formincluding both a corticosteroid and a β-agonist. A preferredpharmacologically active agent for use in accordance with the presentinvention is mometasone furoate.

[0044] To be topically effective in the lungs or the upper and/or lowerairway passages, it is important that the pharmacologically active agentbe delivered as particles of about 10 μm or less. See Task Group on LungDynamics, Deposition and Retention Models For Internal Dosimetry of theHuman Respiratory Tract, Health Phys., 12, 173, 1966. The ability of adosage form to actually administer free particles of thesetherapeutically effectively sized particles is the fine particlefraction. Fine particle fraction is, therefore, a measure of thepercentage of bound drug particles released as free particles of drughaving a particle size below some threshold during administration. Fineparticle fraction can be measured using a multi-stage liquid impingermanufactured by Copley Instruments (Nottingham) LTD using themanufacturer's protocols. In accordance with the present invention, anacceptable fine particle fraction is at least 10% by weight of the drugbeing made available as free particles having an aerodynamic particlesize of 6.8 μm, or less, measured at a flow rate of 60 liters perminute.

[0045] The amount of drug administered will vary with a number offactors including, without limitation, the age, sex, weight, conditionof the patient, the drug, the course of treatment, the number of dosesper day and the like. For mometasone furoate, the amount of drugdelivered per dose, i.e. per inhalation, will generally range from about10.0 μg to about 10,000 μg. Doses of 25 μg, 50 μg, 75 μg, 100 μg, 125μg, 150 μg, 175 μg, 200 μg, 250 μg, 300 μg, 400 μg and/or 500 μg arepreferred.

[0046] The drug may include some or all of the convertible amorphouscontent of the agglomerates as discussed herein.

[0047] The solid binder in accordance with the present invention can beany substance which can be provided in, or reduced to, a particle sizewhich is roughly congruent with the size of the particles of thepharmacologically active agent as previously described. For example,agglomerates of mometasone furoate anhydrous USP will preferably beprovided having particles of at least 80% ≦5 μm and at least 95% ≦10 μm(measured by volume distribution). The solid binder, such as anhydrouslactose, NF will be provided having particles of at least 60% ≦5 μm, atleast 90% under 10 μm, and at least 95% ≦20 μm. The average particlesize is roughly the same for both and is less than 10 μm.

[0048] When in a crystalline form, i.e. when all, or almost all of theconvertible amorphous content of the solid binder converted to acrystalline form, the binder must be stable, capable of supporting andmaintaining an agglomerate and binding particles of therapeuticallyactive agents such that same can be released as a fine particle fractionof particles. The binder must also impart to the crystalline agglomeratea desired range of properties including bulk density, strength, afree-flowing character, and storage stability.

[0049] Preferably, the convertible amorphous content of the solidbinder, if indeed, it contains some or all of the convertible amorphouscontent of the agglomerate, will convert from its amorphous form to itscrystalline form upon exposure to a preselected or predeterminedstimulus such as atmospheric moisture in the form of humidity. However,materials which meet all of the foregoing criteria and will convertresponsive to other preselected stimuli such as, for example,temperature, radiation, solvent vapor and the like may also be used.Preferred solid binders include polyhydroxy aldehydes, polyhydroxyketones, and amino acids. Preferred polyhydroxy aldehydes andpolyhydroxy ketones are hydrated and anhydrous saccharides including,without limitation, lactose, glucose, fructose, galactose, trehalose,sucrose, maltose, raffinose, mannitol, melezitose, starch, xylitol,mannitol, myoinositol, their derivatives, and the like.

[0050] Particularly preferred amino acids include glycine, alanine,betaine and lysine.

[0051] Where the drug is completely crystalline, or where it containsonly non-convertible amorphous content, the solid binder must provideall of the amorphous content of the agglomerate system and vice versa.Neither the solid binder material, nor the drug need naturally have suchan amorphous content, so long as such an amorphous content can bereversibly imparted thereto.

[0052] It is possible that the drug, the binder or both contains acertain percentage of amorphous content which is non-convertible orstable under the conditions of use and storage, as well as when thepreselected stimuli is applied. This stable amorphous content is notpart of the convertible amorphous content previously discussed. As isgenerally the case, this stable amorphous content has some role ininterparticulate binding. However, it will not contribute to theinterparticulate bonding which results from the conversion betweenamorphous and crystalline materials in accordance with the presentinvention.

[0053] Therefore, in certain formulations such as those using, forexample, mometasone furoate, all of the convertible amorphous content iscontributed by the solid binder. As such, sufficient solid binder mustbe provided to impart enough convertible amorphous content to theagglomerate system. However, with another drug such as, for example,albuterol sulfate, which itself can contain convertible amorphouscontent, it may be possible to use a binder with no amorphous content orto use a mixture of a solid binder containing a certain lower percentageof amorphous content along with albuterol. Too much convertibleamorphous content can result in agglomerates which are bound too tightlyto yield the desirable fine particle fraction. Generally, the amount ofamorphous content in the system should range from between about 1 toabout 50% by weight and more preferably between about 3 and 30% byweight. Most preferably, the amount of convertible amorphous content inthe system will range from between about 5 to about 25% by weight. Ofcourse, it is equally acceptable to characterize the amorphous contentof either the binder or the drug, individually, in terms of the percentof amorphous content in the system. Thus, where the binder contains thetotal convertible amorphous content, and where the binder contains a 20%amorphous content and is provided in the 1:1 ratio by weight with thedrug, the total convertible amorphous content in the system will be 10%by weight.

[0054] Some convertible amorphous character can be imparted upon certainmaterial, during the course of reducing the particle size thereof. Thus,for example, if anhydrous lactose is micronized in a micronizer such asMICRON-MASTER® Jet Pulverizer available from the Jet Pulverizer Co.,Palmyra, N.J., it is possible to obtain not only particles of thedesired size, but also to impart a certain amount of amorphous content.-This can also be accomplished using other traditional microparticlegenerating devices such as milling, spray drying or ball milling. SeeBriggner, Buckton, Bystrom and Darcy, “The use of isothermalmicrocalorimetry in the study of changes in crystallinity induced duringthe processing of powders,” International Journal of Pharmaceutics, 105(1994), pp.125-135. However, where others have tried to minimize thedegree of amorphous content generated and have considered this amorphouscontent to be an unfortunate, but generally unavoidable, side effect ofparticle size reduction, the present invention seeks to encourage acertain amount of amorphous content.

[0055] The present invention also seeks to control and maintain thatamorphous character of the solid binder and/or the drug until aspecified time in the agglomeration process. To this end, certain stepsare taken to impart a preselected amount of amorphous character and tomaintain the amorphous character of the solid binder and/or the drug.For example, when anhydrous lactose is pulverized using a Jet Pulverizeras previously discussed, pulverization is carried out under considerablepressure such as, for example, between about 50 and about 120 psig (3.45to 8.27×10⁵ newton/m²). About 80-100 psig (5.51 to 6.89×10⁵ newton/m²)is preferred. The use of such high pressures results in a particularlyviolent particle formation environment and generally increases theamount of amorphous content. Moreover, applicants preferably use drycompressed nitrogen gas to pulverize the solid binder, as applicantshave discovered that the exposure of the amorphous content to humidityduring particle formation can act to reconvert the amorphous contentback to a crystalline form prematurely.

[0056] Of course, it is also possible to impart an amorphous surface toparticles of a solid binder and/or drug which is already of correctparticle size or to use particulate which is inherently amorphous incharacter and can be converted to a crystalline form.

[0057] Once sufficient convertible amorphous content is present, thatamorphous character must be maintained until such time as it isdesirable to convert the particles into completely crystalline form. Forsolid binders or drugs, such as lactose, which are sensitive tohumidity, this can be accomplished by processing and storing under lowhumidity conditions.

[0058] Preferably, the micronized materials are subsequently storedand/or processed under conditions of less than about 30% relativehumidity (“RH”) and more preferably, less than 20% RH at 21° C. By thisit is meant that the micronized materials are processed and stored at anatmospheric moisture content which is equal to that of an atmosphere of30% RH at 21° C., or less. Exact amounts of moisture present in theatmosphere at various temperatures can be derived from Table 5.27, “Massof Water Vapor in Saturated Air,” at page 5.150 of John A. Dean, Lange'sHandbook of Chemistry, Fourteenth Ed., McGraw-Hill, Inc. New York(1992). It is particularly preferable to store any materials containingconvertible amorphous content under humidity conditions of less than 10%RH at 2120 C. and, most preferably, as close to zero relative humidityas practicable. All processing may be carried out at any temperature.However, processing is usually more conveniently carried out between 0°C. and 38° C.

[0059] Generally, any method of agglomerating the solid binder and thepharmacologically active agent, which can be accomplished withoutconverting the amorphous content of the solid binder to a crystallineform, prematurely, and which does not require the use of additionalbinder, can be practiced in accordance with the present invention. Forthis reason, one can generally not practice the agglomeration processesdisclosed in the aforementioned U.S. Pat. No. 4,161,516 as water and/ormoisture are added as a binder prior to agglomeration. This would causethe premature conversion of some or all of the amorphous content to acrystalline form which would actually retard agglomerate formation andlead to variability. This variability could also cause the formation ofagglomerates which are too hard and strong. Even when such agglomeratesare administered using an inhaler which provides a particularly violentdispensing action, these agglomerates may not yield an acceptable fineparticle fraction.

[0060] It is important that the process produce agglomerates ranging insize from between about 100 to about 1500 μm. The agglomerates generallyhave an average size of between about 300 and about 1,000 μm. Morepreferably, the agglomerates have an average size of between about 400and about 700 μm. Most preferably, the agglomerates will have an averagesize of between about 500 and 600 μm. The resulting agglomerates willalso have a bulk density which ranges from between about 0.2 to about0.4 g/cm³ and more preferably, between about 0.29 to about 0.38 g/cm³.Most preferably, the agglomerates will have a bulk density which rangesfrom between about 0.31 to about 0.36 g/cm³.

[0061] It is also important to the dosing of the pharmacologicallyactive agent that the agglomeration process yield a relatively tightparticle size distribution. In this context, particle size refers to thesize of the agglomerates. Preferably, no more than about 10% of theagglomerates are 50% smaller or 50% larger than the mean or targetagglomerate size. Thus for a desired agglomerate of 300 μm, no more thanabout 10% of the agglomerates will be smaller than about 150 μm orlarger than about 450 μm.

[0062] A preferred method of preparing the agglomerates in accordancewith the invention which meets all of the foregoing criteria involvesmixing preselected amounts of one or more pharmacologically activeagent(s) and the micronized, amorphous content containing, dry solidbinder in a ratio of between about 100:1 and about 1:500 and even morepreferably between about 100:1 and about 1:300 (drug:binder) andpreferably a ratio of between 20:1 to about 1:20. Most preferably, thedrug would be provided in an amount of 1:3 to about 1:10 relative to theamount of the solid binder.

[0063] These particles are then preferably mixed in some form ofmechanical mixing device. Preferably, mixing will result in substantialhomogeneity. Of course, it may not be possible for one to obtainabsolute homogeneity. However, a tolerance of ±10% is acceptable duringblending and ±5% is acceptable during agglomeration. Blending suchingredients, in fine particle form, may be a challenge in and of itself.Blending can be accomplished, for purposes of example only, using aPatterson-Kelly V-shape blender having a pin intensifier bar.Preferably, the blending procedure is carried out in the clean room,and, as previously noted, the humidity and temperature of the roomshould be controlled. At 21° C. and 20% RH for example, conversion ofthe amorphous content is sufficiently slow to allow blending. Dependingupon the size of the batch, blending can be accomplished within betweenabout 3 and 15 minutes total. If the mixture of micronized drug andsolid binder will not be further processed immediately, it should againbe stored under low humidity and low temperature conditions.

[0064] For a particularly small amount of drug as relative to the solidbinder, the conventional blending technique may not result in anacceptably homogeneous mixture. In this case, the following approachesmay be used: (1) blending of the drug or drugs and the solid binderbefore micronization; (2) when a mixture of pharmacologically activeagents is used, and particularly when one is present in significantlylarger amounts than the other, blending the two agents together,micronizing the blend and then blending with micronized solid binderhaving a convertible amorphous content; and/or (3) forming microspheresby spray drying, such as: (a) dissolving or suspending the drug in anaqueous solution of a diluent or carrier, such as lactose, spray dryingand then mixing the resulting microspheres with micronized solid binderhaving a convertible amorphous content; or (b) spray drying a nonaqueoussolution or suspension of drug, containing suspended, micronized diluentor carrier particles, such as lactose, then mixing with solid binderparticles having a convertible amorphous content. In fact, even withlarger amounts of drug, it may be desirable to employ the firstapproach.

[0065] From the blender, the mixed particles are poured into aconventional screen/pan combination for agglomerate formation. Theparticles can now be thought of as an agglomeration as they no longerretain as much of their individual identity. They are not “agglomerates”as described herein as they are not smaller, individualized collectionsof particles of generally spherical shape and/or greater density.

[0066] Screen and pan are then rotated in an eccentric circular motionin a plane parallel to the ground. This can be done manually or using ascreen shaking device. An intermittent tapping is appliedperpendicularly to the top of the pan which forces or meters materialsthrough the screen into the pan below where the eccentric motion of thepan encourages agglomerate formation as defined previously. Theagglomerates are also simultaneously spheronized. Of course, thisagglomeration procedure, as with any agglomeration procedure inaccordance with the present invention, must be carried out under lowhumidity conditions to prevent the unwanted, premature conversion of theamorphous content of the solid binder to crystalline form.

[0067] After the agglomerates are formed and properly sized by, forexample, pouring through another screen, they can be exposed to apreselected stimuli, such as higher humidity, to cause the substantiallycomplete conversion of the convertible amorphous content containedwithin the agglomerates to a crystalline form.

[0068] Of course, the higher the humidity, the less the amount of timenecessary for exposure. However, a somewhat gradual and controlledconversion is preferred as the strength of the agglomerates is to betightly controlled. Agglomerates containing convertible amorphouscontent can be exposed to relative humidity of between about 30% andabout 80% (at 25° C.) for a time period which is sufficient to convertthe entire amorphous content. More preferably, the convertible amorphouscontent is converted by exposure to an atmosphere having a water contentequal to a relative humidity of between about 40% and about 60%(measuring the relative humidity at about 25° C.). This is particularlyuseful when the solid binder is anhydrous such as anhydrous lactose. Theamount of time can vary dramatically with the size and density of theagglomerates and the surface area of exposure. For example, placing athin layer of agglomerates on a flat open tray will yield a much fasterconversion overall than placing the same quantity of agglomerate in anarrow jar. In certain cases, the length of exposure need be on theorder of tens of minutes. In other instances, one to two days may berequired.

[0069] Because, preferably, the exposure is controlled to relativehumidities of 65% or below (at 25° C.), there is relatively littleconcern about overexposure. So long as sufficient time is provided toallow all of the convertible amorphous content of the agglomerates toconvert to crystalline form, the fact that additional exposure may takeplace is generally not of any consequence. If humidity levels aboveabout 65% are used, however, then the water vapor can actually act as abinder. While the use of water as a binder is well known, it isdetrimental to the ability to generate a fine particle fraction,particularly when used in combination with the principal mode of bindingdescribed herein; namely crystalline binding. Therefore, it is stilldesirable to limit the exposure of the agglomerates to elevated humiditylevels beyond the point necessary for complete conversion. Afterconversion, the agglomerates have an interparticulate bonding strengthwhich is measurably greater than the interparticulate bonding strengthprior to conversion.

[0070] The agglomerates that result are, as previously described,generally crystalline in nature, free-flowing, rugged and resistant tohang up. These agglomerates can be stored, handled, metered anddispensed while maintaining their structural integrity. The agglomeratesalso have a very desirable and consistent size and size distribution.Perhaps most importantly, the crystalline agglomerates of the presentinvention have sufficient strength to allow them to be handled andabused. At the same time, the agglomerates remain soft enough to bebroken sufficiently during dosing so as to provide an acceptable fineparticle fraction. In general, the agglomerates have a strength whichranges from between about 50 mg and about 5,000 mg and most preferablybetween about 200 mg and about 1,500 mg. The crush strength was testedon a Seiko TMA/SS 120C Thermomechanical Analyzer available from SeikoInstruments, Inc. Tokyo, Japan, using procedures available from themanufacturer. It should be noted that strength measured in this manneris influenced by the quality and extent of the interparticulatecrystalline bonding described herein. However, the size of theagglomerates also plays a role in the measured crush strength.Generally, larger agglomerates require more force to crush than do thesmaller particles.

[0071] When agglomerates produced in accordance with the protocolreported in Example 1 were dosed at 100 μg per inhalation using a powderinhaler as described in WO 94/14492 assigned to Schering Corporation,sufficiently violent force was generated so as to break up theagglomerates enough to yield the desired level of free drug particleshaving a size of about 6.8 μm or less. Of course, the degree of forcewhich must be generated while the agglomerates are dispensed isdependent upon the internal bond strength of the agglomerates. Thegreater the bond strength, the greater the amount of force which will berequired to yield an acceptable fine particle fraction. The agglomeratesof the present invention, while too strong and stable for certaininhalers are, nonetheless, useful in other commercially availableinhalers and, when dispensed from same, an acceptable fine particlefraction results. Such inhalers include, without limitation, Schering'sinhaler as identified above, Diskhaler (Allen & Hanburys), Accuhaler(Allen & Hanburys), Diskus (Glaxo), Spiros (Dura), Easyhaler (Orion),Cyclohaler (Pharmachemie), Cyclovent (Pharmachemie), Rotahaler (Glaxo),Spinhaler (Fisons), FlowCaps(Hovione), Turbospin (PH&T), Turbohaler(Astra), EZ Breath (Norton Healthcare/IVAX), MIAT-HALER (Miat), Pulvinal(Chiesi), Ultrahaler (Fisons/ Rhone Poulenc Rorer), MAG-Haler (GGU),Prohaler (Valois), Taifun (Leiras), JAGO DPI (JAGO), M L Laboratories'DPI (M L Laboratories).

[0072] The inhaler must be capable of producing sufficient force tobreak up whatever agglomerate is used so as to produce an acceptablefine particle fraction. Therefore, an agglomerate having a crushstrength of 1,000 mg as measured in the manner described herein, must beused in combination with an inhaler that can apply sufficient force toensure that at least a 10% fine particle fraction results from each dosetherefrom.

[0073] As shown in FIG. 1, mometasone:anyhydrous lactose agglomerates ofa ratio of 1:5.8 (by weight) were exposed to 50% relative humidity at25° C. both before and after conversion. The graph using the unbrokenline (I) demonstrates the moisture uptake of the agglomerates whenexposed to humidity before the agglomerates are converted to crystallineform. Moisture is absorbed very quickly reaching a maximum point. Atthat point, conversion to the crystalline form takes place. As theresult of that conversion, water is actually expelled and the overallmoisture content drops. By the same token, once agglomerates which havebeen converted are exposed to moisture, they may absorb a small amountof moisture, but thereafter, moisture uptake is flat. See broken line(II). Amongst other things, FIG. 1 demonstrates the resulting stabilityof the agglomerates which are formed in accordance with the presentinvention.

[0074] The discovery and use of the increasing bond strength of thecrystalline agglomerates is significant for a number of reasons. Firstthe resulting agglomerates are free-flowing, stable, and able to behandled and packaged appropriately. Second, the agglomerates provide thenecessary homogeneity and bulk density to allow them to be consistentlyloaded into the dose hole of an inhaler, even in particularly smalldoses. Thus the crystalline agglomerates can be accurately metered,measured and delivered. This is aptly demonstrated in FIG. 2. When theprocess of the present invention was carried out on lactose alone, andwhen humidity was added to the lactose prior to agglomeration, theresulting lactose agglomerate proved to be too soft to handle.Significant problems in repeatable dosing would thus be realized. Thesesame results were observed when mixtures of drug and lactose wereexposed to humidity prior to agglomeration.

[0075] In fact, in formulating a batch in accordance with the presentinvention as described in Example 1, anhydrous lactose was used that hadalready been converted. That fact was not known at the time. When theresulting agglomeration protocol did not yield the desired results, thecause was investigated. The prior conversion of the lactose wassubsequently discovered. Thus, it is important to maintain theconvertible amorphous content of the drug and/or binder in that stateuntil after the formation of agglomerates as described herein.

[0076] In another experiment also illustrated in FIG. 2, mometasonecontaining agglomerates were filled into an inhaler prior tostabilization with humidity. The final product was not stable andprovided poor dose delivery due to high hang up in the nozzle of theinhaler and elsewhere. When the same drug containing agglomerates werestabilized by exposure to humidity as discussed herein, the resultingagglomerates were hard, free-flowing and easily handled. The internalbond strength was increased, allowing for proper handlingcharacteristics. Yet the agglomerates remained soft enough to yield anacceptable fine particle fraction.

[0077] The present invention results in a higher degree of dosinguniformity. As shown in Table 1, agglomerates produced in accordancewith the present invention were loaded into 10 inhalers as described inthe aforementioned WO 94/14492. The inhalers were set to deliver 100 μgof mometasone furoate per inhalation. Mometasone furoate was provided ina ratio 1:5.8 to anhydrous lactose (680 μg total agglomerate) and wereproduced as described in Example 1. TABLE 1 Dose Uniformity Over theLabeled Number Of Inhalations (Emitted Dose) Initial Unit Dose MiddleUnit Dose Final Unit Dose Inhaler Inhalation 1 Inhalation 60 Inhalation120 Number (μg) (μg) (μg) 1 91 101 98 2 91 96 93 3 99 89 90 4 88 100 1005 105 100 96 6 95 95 96 7 106 106 96 8 92 96 89 9 109 100 93 10 90 95100 Average 97 98 95 % CV ** 7.9 4.7 4.0

[0078] The emitted dose was determined using a Dosage Unit SamplingApparatus for Dry Powder Inhalers similar to that described inPharmaceutical Forum, Vol. 20, No. 3, (1994) pp. 7494. The emitted dosewas collected using a separatory nel attached at one end to a sinteredglass filter at an air flow rate of 60 L/minute for a total of 4seconds. The drug was then dissolved in a solvent and analyzed usingHPLC as is known in the art. It is clearly evident from a review ofTable 1 that from a first inhalation dose, through the 120th, there isgreat consistency. In addition, the consistency from inhaler to inhaleris significantly higher than one would normally expect. Perhaps mostimportantly, the average over all 120 doses for 10 inhalers shows greatconsistency. These numbers also indicate that very little material islost during dosing. Thus, hang-up and dosing problems resulting fromfilling the dosing hole are minimized.

[0079] The fine particle fraction (as a percentage of the total dose)resulting from these emitted doses was also tested (Table 2). The fineparticle fraction (≦6.8 μm) was determined at a 60 L/minute flow rateusing a multi-stage (5-stage) liquid impinger manufactured by CopleyIndustries (Nottingham) LTD. TABLE 2 Inhaler Initial Unit Dose MiddleUnit Dose Final Unit Dose Number Inhalation 1 Inhalation 60 Inhalation120 1 28 24 25 2 19 21 22 3 27 25 22 Average 24 23 23

[0080] The measured fine particle fraction from each inhaler was greaterthan 10% and, in addition, was greatly uniform from the first dosethrough dose 120.

[0081] A multi-stage impinger allows one to measure the fraction ofcertain sized particles in each of its various stages. As illustrated inTable 3, there is great uniformity between dose 1 and dose 120 in termsof the cumulative fine particle fraction which are less than the 13 μm,less than 6.8 μm, less than 3.1 μm and less then 1.7 μm. TABLE 3Particle size Initial Dose* Middle Dose* Final Dose* (μm) Inhalation 1Inhalation 60 Inhalation 120 <13.0 28 26 26 <6.8 24 23 23 <3.1 15 16 16<1.7 7 8 8

[0082] Finally, as shown in FIGS. 3 and 4, the agglomerates of thepresent invention are very durable. FIG. 4 illustrates the control. Inthis case, it illustrates, graphically, the percent of weight deliveredor the emitted dose, in weight percent, of 10 inhalers over 120 doseseach. The inhalers used were the Schering powder inhaler previouslyidentified and the doses were 100 μg of mometasone furoate with ananhydrous lactose binder produced as described in Example 1. FIG. 3presents the same data, for identically configured inhalers, after theyhad been dropped onto a hard surface from a height of about 122 cm (48inches). A comparison of the results memorialized in FIGS. 3 and 4 showthat very little change is exhibited overall.

[0083] The present invention helps ensure an unprecedented degree ofagglomerate uniformity which significantly reduced the variability ofdosing as previously demonstrated. For example, if moisture is addedprior to or during agglomeration, a certain percentage of the solidbinder will begin to convert to a crystalline form. The degree ofcrystal formation can vary greatly from particle to particle. As aresult, the size of the agglomerate and the physical strength of theinterparticulate bonding can vary greatly. In addition, the binder canactually begin to dissolve and this would create bonds which are toostrong. This immediately translates into dose variability duringinhalation and a variability in the terms of the fine particle fractionof drug delivered. The present invention overcomes this problem andefficiently provides uniform agglomerates which are easy to produce,store, handle and administer.

EXAMPLES Example 1

[0084] To ensure the quality and uniformity of the product, theenvironmental conditions for handling and manufacturing agglomerates inaccordance with the present invention were as follows:

[0085] Micronization of mometasone and lactose: 21° C. ±2° and 20% RH±5%

[0086] Storage of micronized lactose: 21° C. ±2° and less than 15% RH

[0087] Powder blending and agglomeration: 21° C. ±2° and 20% RH ±5%

[0088] Conversion of powder agglomerates: 25° C. ±2° and 50% RH ±5%

[0089] A Patterson-Kelley V-shape blender installed with a pinintensifier bar was set-up in a clean room with temperature and humiditycontrolled at 21° C. and 20% RH, respectively. Half of the micronizedlactose anhydrous was charged into the V-blender. The micronizedmometasone furoate anhydrous was added next. Then, the balance of themicronized lactose anhydrous was added.

[0090] The V-blender was turned on for 5 minutes at a rotation speed ofabout 24 RPM. Next, the V-blender was rotated for 3 minutes with the pinintensifier bar turned on for the first 1 minute at a pin tip speed ofabout 9 meters/second. The blending protocol was then repeated.

[0091] Samples were taken from right, left, and bottom of the V-blenderto test the blend uniformity using a unit-dose sampling thieve.

[0092] To agglomerate this mixture, a screen shaker was set up in aclean room with temperature and humidity controlled at 21° C. and 20%RH, respectively. Thirty (30) mesh screens, pans, and stainless-steelcontainers were washed with 70% alcohol and dried.

[0093] Screen/pan combinations were assembled and placed on the shaker.Into each 12 inch, 30 mesh screen/pan set, 200 g of themometasone:anhydrous lactose blend in a ratio of 1:5.8 (drug:binder) wasadded. The powder blend was spread on the screen so that the level ofthe powder blend was lower than the edge of the sieve frame. Thescreen/pan was placed on the sieve support plate of the shaker. Astainless-steel sieve cover was placed on the top screen.

[0094] The timer was then set for 10 minutes and the device was turnedon such that an eccentric circular shaking with a one inch eccentricorbit at a speed of about 280 rpm occurred. The screen/pan was alsotapped at a rate of 150 taps/minute to meter material through thescreen. The process was stopped and multiple pans consolidated.

[0095] The agglomerates formed were poured onto a 20 mesh screen and thescreen was tapped lightly. The material retained on the 20 mesh screenwas discarded.

[0096] The agglomerates which passed through the 20 mesh screen werestored in the suitable containers.

[0097] When ready to convert the material, the agglomerates were spreadonto a stainless-steel tray and exposed in a clean room having atemperature and humidity controlled at 25° C. and 50% RH, for 24 hours.The agglomerates were then combined and placed in a suitable container.

[0098] The bulk density was determined using a Vanderkamp Tap DensityTester set for one tap. Particle size distribution of the agglomerateswas determined using a Malvern 2605L particle size analyzer.

Example 2

[0099] Three additional batches were produced in accordance with theprocess generally described in Example 1. The batch size and drug tobinder ratios are illustrated below in Table 4: TABLE 4 REPRODUCIBILITYOF MOMETASONE: LACTOSE AGGLOMERATES MMF: BULK PARTICLE SIZE DISTRIBUTIONBULK LACTOSE DENSITY DIAMETER (μm) UNDER SIZE RATIO (g/cm³) 10% 50% 90%mean 0.75 Kg 1:5.8 0.35 420 540 790 580 9.60 Kg 1:5.8 0.35 370 510 740540 9.60 Kg 1:19 0.35 390 540 770 570

[0100] As will be readily appreciated, despite varying ratios of binderand drug, as well as varying batch sizes, a high degree of repeatabilitywas observed in terms of bulk density and particle size distribution.Particle size in this context refers to the size of the agglomeraterather than that of the particulate binder and/or drug.

What is claimed is:
 1. A process of producing agglomerates comprisingthe steps of: (a) providing particles of at least one first material andparticles of at least one solid binder, at least one of said firstmaterial and said solid binder having a preselected amount ofconvertible amorphous content which is capable of being converted tocrystalline form upon exposure to a preselected stimulus, saidconvertible amorphous content being provided in an amount which issufficient to allow for the formation of agglomerates; (b) agglomeratingsaid particles of said first material and said solid binder whilemaintaining said preselected amount of convertible amorphous content;and thereafter (c) exposing said convertible amorphous content withinsaid agglomerates to said preselected stimulus so as to convert saidconvertible amorphous content to a crystalline form.
 2. The process ofclaim 1 wherein said first material comprises a pharmacologically activeagent.
 3. The process of claim 2 wherein said pharmacologically activeagent comprises at least one member selected from the group consistingof corticosteroids, β-agonists, anticholinergics, leukotrieneantagonists and inhalable proteins or peptides.
 4. The process of claim2, wherein said pharmacologically active agent comprises at least onemember selected from the group consisting of: mometasone furoate;beclomethasone dipropionate; budesonide; fluticasone; dexamethasone;flunisolide; triamcinolone; salbutamol; albuterol; terbutaline;salmeterol; bitolterol; ipratropium bromide; oxitropium bromide; sodiumcromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol;eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol;(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy4-pregnen-3,20-dione;TA-2005; tipredane; insulin; interferons; calcitonins; parathyroidhormones; and granulocyte colony-stimulating factor.
 5. The process ofclaim 2, wherein said pharmacologically active agent comprisesmometasone furoate.
 6. The process of claim 2, wherein said particles ofsaid pharmacologically active agent have an average particle size of 10μm or less.
 7. The process of claim 1, wherein said solid bindercomprises at least one member selected from the group consisting ofpolyhydroxy aldehydes, polyhydroxy ketones, and amino acids.
 8. Theprocess of claim 1, wherein said solid binder comprises a hydrated oranhydrous saccharide.
 9. The process of claim 1, wherein said solidbinder comprises anhydrous lactose or a hydrated lactose.
 10. Theprocess of claim 1 wherein said solid binder comprises anhydrouslactose.
 11. The process of claim 2, wherein said particles of saidsolid binder have an average particle size of 10 μm or less.
 12. Theprocess of claim 2, wherein said agglomerate contains between about 1%and about 50% convertible amorphous content.
 13. The process of claim 2,wherein said agglomerate contains between about 3% and about 30%convertible amorphous content.
 14. The process of claim 2, wherein saidagglomerate contains between about 5% and about 25% convertibleamorphous content.
 15. The process of claim 2, further comprising thestep of mixing said particles of pharmacologically active agent and saidsolid binder prior to said agglomerating step.
 16. The process of claim14, wherein said particles of pharmacologically active agent and saidsolid binder are mixed to substantial homogeneity.
 17. The process ofclaim 2, wherein said particles of pharmacologically active agent andsaid solid binder are agglomerated in a pan rotated with an eccentricmotion.
 18. The process of claim 2, wherein said agglomerates have anaverage size of between about 300 and about 1000 μm.
 19. The process ofclaim 2, wherein said agglomerates have a range in size from betweenabout 100 and about 1500 μm.
 20. The process of claim 1 wherein saidpreselected stimulus is atmospheric moisture.
 21. The process of claim1, wherein said solid binder is maintained at a moisture content of lessthan or equal to that of a relative humidity of 25% when measured at 21°C., prior to crystallization.
 22. The process of claim 1, wherein saidsolid binder is maintained at a moisture content of less than or equalto that of a relative humidity of 20% when measured at 21° C., prior tocrystallization.
 23. The process of claim 2, further comprisingconverting said convertible amorphous content of said agglomerate into acrystalline form by exposure of said agglomerates to an atmospherehaving a moisture content equal to that of a relative humidity ofbetween about 30% and about 80% when measured at 25° C.
 24. The processof claim 23, wherein said convertible amorphous content is convertedinto a crystalline form by exposure of said agglomerates to anatmosphere having a moisture content equal to that of a relativehumidity of between about 40% and about 60% when measured at 25° C. 25.The process of claim 2, wherein said particles of said agglomerate aremore strongly bound to one another after conversion of said amorphouscontent to a crystalline form than before conversion.
 26. The process ofclaim 2, wherein said agglomerates have a crush strength of betweenabout 50 mg and about 5,000 mg after conversion of said convertibleamorphous content.
 27. The process of claim 2, wherein said agglomerateshave a crush strength of between about 200 mg and about 1,500 mg afterconversion of said convertible amorphous content.
 28. The process ofclaim 1, further comprising the step of micronizing said solid binderand/or said first material to impart thereto a preselected amount ofamorphous content to the resulting particles prior to the step ofproviding said particles.
 29. The process of claim 28, wherein saidsolid binder is micronized using jet milling with a substantiallyanhydrous gas.
 30. The process of claim 2, wherein saidpharmacologically active agent and said solid binder are mixed at aweight ratio of between about 1000:1 to 1:1000.
 31. The process of claim2, wherein said pharmacologically active agent and said solid binder aremixed at a weight ratio of between about 100:1 to 1:500.
 32. The processof claim 2, wherein said pharmacologically active agent and said solidbinder are mixed at a weight ratio of between about 100:1 to 1:300. 33.The process of claim 2, wherein said pharmacologically active agent andsaid solid binder are agglomerated at a weight ratio of between about20:1 to about 1:20.
 34. The process of claim 2, wherein saidpharmacologically active agent and said solid binder are agglomerated ata weight ratio of between about 1:3 to about 1:10.
 35. The product ofthe process of claim
 1. 36. The product of the process of claim
 2. 37.The product of the process of claim
 3. 38. A process for producingagglomerates containing a pharmacologically active agent, comprising thesteps of: (a) providing at least one pharmacologically active agenthaving an average particle size of below about 10 μm; (b) providing atleast one solid binder having an average particle size of about 10 μm orbelow; at least one of said pharmacologically active agent and saidsolid binder having a preselected amount of convertible amorphouscontent which is sufficient to allow for the formation of agglomeratesupon conversion; (c) forming a homogeneous mixture of said particles ofsaid pharmacologically active agent and said solid binder whilemaintaining said preselected amount of convertible amorphous content;(d) agglomerating said mixture of said particles of saidpharmacologically active agent and said solid binder while maintainingsaid preselected amount of convertible amorphous content of said solidbinder; and (e) thereafter allowing said convertible amorphous contentof said agglomerates to convert to a crystalline form; to form (f)agglomerates which are free-flowing, have bridges and are characterizedby having a strength of between 50 mg and 5000 mg.
 39. The process ofclaim 38 wherein said pharmacologically active agent comprises at leastone member selected from the group consisting of corticosteroids,β-agonists, anticholinergics, leukotriene antagonists and inhalableproteins or peptides.
 40. The process of claim 38, wherein saidpharmacologically active agent comprises mometasone furoate
 41. Theprocess of claim 38, wherein said solid binder comprises anhydrouslactose or a hydrated lactose.
 42. The process of claim 38, wherein saidagglomerate contains between about 1% and about 50% convertibleamorphous content prior to conversion.
 43. The process of claim 38,wherein said agglomerate contains between about 3% and about 30%convertible amorphous content prior to conversion.
 44. The process ofclaim 38, wherein said agglomerate contains between about 5% and about25% convertible amorphous content prior to conversion.
 45. The processof claim 38, wherein said agglomerates have a strength of between 200 mgand about 1500 mg.
 46. A dosage form of a pharmacologically active agentuseful for administration by oral inhalation therapy consistingessentially of: agglomerates of particles of a pharmacologically activeagent and particles of crystalline solid binder, said particles havingan average particle size of 10 μm or less and being provided in a weightratio of between 100:1 to 1:500, said agglomerates having an averagesize of between 400 and 700 μm, a bulk density of between about 0.2 andabout 0.4 g/cm³ and a crush strength of between 200 mg and about 1500mg.
 47. The dosage form of claim 46, wherein said crystalline solidbinder comprises lactose.
 48. The dosage form of claim 47, wherein saidcrystalline lactose comprises anhydrous lactose.
 49. The dosage form ofclaim 46, wherein said agglomerates have a bulk density of between about0.29 and about 0.38 g/cm³.
 50. The dosage form of claim 46 wherein saidpharmacologically active agent comprises at least one member selectedfrom the group consisting of corticosteroids, β-agonists,anticholinergics, leukotriene antagonists and inhalable proteins orpeptides.
 51. The dosage form of claim 46, wherein saidpharmacologically active agent comprises at least one member selectedfrom the group consisting of: mometasone furoate; beclomethasonedipropionate; budesonide; fluticasone; dexamethasone; flunisolide;triamcinolone; salbutamol; albuterol; terbutaline; salmeterol;bitolterol; ipratropium bromide; oxitropium bromide; sodiumcromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol;eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol;(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy-4-pregnen-3,20-dione;TA-2005; tipredane; insulin; interferons; calcitonins; parathyroidhormones; and granulocyte colony-stimulating factor.
 52. The dosage formof claim 46 wherein said agglomerate includes no binder other than saidsolid binder.
 53. An intermediate agglomerate useful for producing afree-flowing crystalline agglomerate dosage form of a pharmacologicallyactive agent useful for administration by oral or nasal inhalationtherapy, said intermediate agglomerates comprising: particles of saidpharmacologically active agent and particles of solid binder, saidpharmacologically active agent or said solid binder having a preselectedamount of convertible amorphous content which is sufficient to allow forthe formation of crystalline agglomerates upon exposure to moisture,said particles of said pharmacologically active agent and said particlesof said solid binder having an average particle size of 10μm or less,and said particles being provided in a weight ratio of between 1000:1 to1:1000.
 54. The intermediate agglomerate of claim 53 having an averagesize of between 300 and 1000 μm, and a bulk density of between about 0.2and about 0.4 g/cm³.
 55. The intermediate agglomerate of claim 53,wherein said lactose comprises anhydrous lactose.
 56. The dosage from ofclaim 53, having a bulk density of between about 0.29 and about 0.38g/cm³.
 57. The intermediate agglomerate of claim 53, having an averagesize of between 400 and about 700 μm.
 58. The intermediate agglomerateof claim 53 wherein said pharmacologically active agent comprises atleast one member selected from the group consisting of corticosteroids,β-agonists, anticholinergics, leukotriene antagonists and inhalableproteins or peptides.
 59. The intermediate agglomerate of claim 53,wherein said pharmacologically active agent comprises at least onemember selected from the group consisting of: mometasone furoate;beclomethasone dipropionate; budesonide; fluticasone; dexamethasone;flunisolide; triamcinolone; salbutamol; albuterol; terbutaline;salmeterol; bitolterol; ipratropium bromide; oxitropium bromide; sodiumcromoglycate; nedocromil sodium; zafirlukast; pranlukast; formoterol;eformoterol; bambuterol; fenoterol; clenbuterol; procaterol; broxaterol;(22R)-6α,9α-difluoro-11β,21-dihydroxy-16α,17α-propylmethylenedioxy4-pregnen-3,20-dione;TA-2005; tipredane; insulin; interferons; calcitonins; parathyroidhormones; and granulocyte colony-stimulating factor.
 60. Theintermediate agglomerate of claim 63, having a convertible amorphouscontent of between about 1 and about 50% by weight.
 61. A dosing systemcomprising: (a) an inhaler, said inhaler including a storage reservoirfor storing an amount of a pharmacologically active agent in the form ofa crystalline agglomerate, sufficient to provide a plurality ofindividual doses thereof, a metering device for measuring and metering apreselected amount of said pharmacologically active agent from saidstorage reservoir, and a nozzle for conveying said pharmacologicallyactive agent from said metering device to the mouth or nose of apatient; and (b) an amount of a pharmacologically active agentsufficient to provide a plurality of individual doses thereof, saidpharmacologically active agent being stored within said storagereservoir, being provided as an agglomerate of particles of saidpharmacologically active agent and particles of a crystalline binder,wherein said particles have an average particle size of 10 μm or lessand the components thereof are provided in a weight ratio of between1000:1 to 1:1000, said agglomerates having an average size of between300 and 1000 μm and a bulk density of between about 0.2 and about 0.4g/cm³; and said agglomerate and said inhaler, when used in combination,being capable of producing a fine particle fraction of at least 10%, atan inhaled air flow rate about 60 L/min.
 62. The dosing system of claim61, wherein said crystalline agglomerates have a strength of betweenabout 50 mg and about 5000 mg and wherein said inhaler is designed suchthat it will impart to said agglomerated pharmacologically active agentan amount of force which is sufficient to produce a fine particlefraction of at least 10%, at an inhaled air flow rate about 60 L/min.63. The dosing system of claim 61, wherein said crystalline agglomerateshave a strength of between about 200 mg and about 1,500 mg and whereinsaid inhaler is designed such that it will impart to said agglomeratedpharmacologically active agent an amount of force which is sufficient toproduce a fine particle fraction of at least 10%, at an inhaled air flowrate about 60 L/min.